FEBRUARY 2009 VOLUME 22, NUMBER 2 Copyright 2009 by the American Chemical Society
Editorial Introduction: Human Metabolites in Safety Testing (MIST) Issue The metabolism of drugs is a very important component of safety assessment, a major element of drug development. The appropriate selection of experimental animal models is critical in predicting risks for humans, and achieving multiples of human exposure to the drug in an animal species is an important element in safety assessment. In the past 20 years, the use of in vitro studies has been developed to predict which animal species best matches the metabolism in humans. However, in some cases, the metabolism pattern in humans may not match that in any of the common experimental animal species used for testing, and we have the issue of “human-specific metabolites”. In many cases, it may not be an issue of “all or none” (specificity) but a quantitative issue. Pharmaceutical companies have always been concerned about this issue, that is, achieving multiples of not only the parent drug but also all human metabolites in appropriate animal test species. The issue of human “metabolites in safety testing” (MIST) has been debated in the United States by the Food and Drug Administration (FDA) and pharmaceutical companies (see the 2006 Chemical and Research in Toxicology Forum) (1-4). In February, 2008, the FDA issued the Guidance for Industry: Safety Testing of Drug Metabolites (http://www.fda.gov/CDER/ GUIDANCE/6897ful.pdf). Any human drug metabolite “...formed at greater than 10 percent of parent drug systemic exposure at steady state” is subject to separate safety testing, that is, by synthesis and administration to test animals. As stated in the Guidance, comparison between human and animal exposure generally is based upon the (pharmacokinetic) area under the curve, an in vivo parameter. The decision to use a percentage (as opposed to mass) has been debated, and concerns have also been raised about pharmacokinetic issues related to administration of metabolites and achievement of levels in target tissues (1-4 and references therein). In this issue, we feature 13 papers on the subject, from both academic and industrial scientists involved with these issues. The papers include a mixture of reviews, perspectives, and original research articles. Some of the papers deal with the use of NMR and mass spectrometry in the assessment and quanti-
tation of metabolites (Espina, p 299; Mutlib, p 311; and Baillie, p 263). Four papers involve retrospective considerations and relevance for future prediction (Leclercq, p 280; Knadler, p 243; Smith, p 267; and Isoherranen, p 294). Two papers deal with predictions of genotoxic hepatotoxic metabolites (Dobo, p348; and Bauman, p 332). Two approaches are presentedsone a comparison of three in vitro systems for predicting human metabolites (Dalvie, p 357) and the other in vivo humanized transgenic mouse models for doing the same (Powley, p 257). One study presents the use of a rapid electrochemical approach to screening adduct formation in animal vs human systems (Rusling, p 341). Finally, a study implicating human P450 1A2 in generating species-specific reactive metabolites of a drug is included (Kuribayashi, p 323). The issue of human-specific metabolites is a complex one, and much remains to be learned. A symposium on the topic will be presented at the 2009 Fall National Meeting of the American Chemical Society (Washington, DC, August 16-19), cosponsored by the Divisions of Chemical Toxicology and Medicinal Chemistry. Human-specific metabolites that fall under the FDA MIST guidelines are not unusual. Testing of these is not inexpensive, and as one will learn from reading the papers published here, the strategies for predicting which drug candidates will generate human-specific metabolites and how to design the relevant experiments are not standard. This is certainly a field in which more insight is needed. We hope that this collection of papers will not only serve as an introduction to the topic for novices to the area and a useful reference for those already involved but also serve as a stimulus to these and others to develop new approaches to the problem. F. Peter Guengerich Associate Editor
References (1) Guengerich, F. P. (2006) Safety assessment of stable drug metabolites. Chem. Res. Toxicol. 19, 1559–1560.
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(2) Davis-Bruno, K. L., and Atrakchi, A. (2006) A regulatory perspective on issues and approaches in characterizing human metabolites. Chem. Res. Toxicol. 19, 1561–1563. (3) Humphreys, G. H., and Unger, S. E. (2006) Safety assessment of drug metabolites: Characterization of chemically stable metabolites. Chem. Res. Toxicol. 19, 1564–1569.
(4) Smith, D. A., and Obach, R. S. (2006) Metabolites and safety: What are the concerns and how should we address them? Chem. Res. Toxicol. 19, 1570–1579.
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